The Vitamin D Pathway and Mammographic Breast Density in Postmenopausal Women Abstract Laboratory studies have demonstrated that Vitamin D has a number of chemopreventive properties. However, epidemiologic data exploring the effects of Vitamin D on breast cancer risk are limited and inconsistent. While many studies have assessed dietary intake, fewer have directly measured blood levels of Vitamin D in relation to breast cancer risk. None have explored Vitamin D in the full context of other molecules, such as retinol, which laboratory studies suggest influence the effect of Vitamin D on breast cells. Further, downstream targets of Vitamin D with chemopreventive or mitogenic properties, such as parathyroid hormone and IGF-1, may themselves influence breast cancer risk. The objective of this study is to evaluate the Vitamin D pathway in relation to mammographic breast density, an intermediate marker of breast cancer risk. We propose to 1) examine the relation between mammographic density and blood levels of Vitamin D;2) determine the potential role of parathyroid hormone, IGF-1, and IGFBP-3 in mediating the association between Vitamin D and density;and 3) determine if the relation between mammographic density and Vitamin D is modified by blood levels of retinol or calcium. To accomplish these aims, we propose to add additional exposure assessment to our existing research study evaluating breast density among 270 healthy postmenopausal women attending University of Wisconsin-Madison Clinics for a screening mammogram. Data collection for this existing study includes a breast cancer risk factor questionnaire and a blood sample, both obtained at the time of the mammogram. Mammographic density will be assessed as a continuous linear function measuring percent density, using a computer-assisted method (Cumulus software). We propose to supplement this existing study by measuring serum levels of Vitamin D [25(OH)D], parathyroid hormone, IGF-1, IGFBP-3, retinol, and calcium. Statistical methods will be used to determine the relation between mammographic density and Vitamin D, the potential mediating roles of parathyroid hormone, IGF-1, and IGFBP-3, and the potential modifying effects of retinol and calcium. Adding Vitamin D exposure assessment to the parent study will effectively leverage existing investment of research funds. By using mammographic density on a continuous scale as an intermediate marker, this study offers an efficient design with strong power to detect an association between breast density and levels of potentially important and modifiable Vitamin D pathway molecules. Since Vitamin D insufficiency in the United States is widespread and increasing, evidence elucidating the relevance of Vitamin D to breast cancer risk may point to important strategies for breast cancer prevention. PUBLIC HEALTH RELEVANCE: The Vitamin D Pathway and Mammographic Breast Density in Postmenopausal Women Narrative Laboratory studies have demonstrated that Vitamin D has anti-carcinogenic properties, and breast tissue is known to contain Vitamin D receptors. We plan to measure blood levels of Vitamin D and other molecules which interact with Vitamin D in a group of 270 women who are already enrolled in a study of mammographic breast density. Since breast density is a strong intermediate marker of breast cancer risk, an association between Vitamin D and breast density would suggest a potential role for Vitamin D in the prevention of breast cancer.